Introduction To Toxicology Presented by : Pharm.D: Fatimah Al.Shehri 2014 Newly graduated pharmacist King Abdul-Aziz university .

Objectives : - Origin of toxicology . - Definitions of some toxicological terms . - Branches of toxicology . - Classifications of toxicological agents . - Factors that affect toxicity . - Dose response relationship.

Origins of Toxicology -Earliest humans used animal venoms and plant extracts for hunting, warfare and assassination. -400 BC: Hippocrates compiled a listing of a number of poisons and outlined some clinical toxicology principles. :-1493-1541: Paracelsus—physician and philosopher All substances are poisons; the right dose differentiates a poisons from a remedy. Dose determines toxicity.

Examples of toxicological cases 399 B.C. Socrates, a Greek Philosopher died of Hemlock poisoning (according to Plato) -Coniine is the active toxic ingredient -Antagonist for the nicotinic acetylcholine receptor, leading to cessation of neurotransmission, muscular and respiratory collapse and death. October 20th, 1740 Charles VI, Holy Roman Emperor, King of Bohemia, Hungary, and Croatia died from eating death cap mushrooms. -Active ingredient is alpha-amanitin that inhibits -RNA polymerase inhibiting protein synthesis leading to hepatocellular lysis, liver failure, kidney failure, coma, respiratory failure, and death

Examples of toxicological cases April 30th, 1945, Eva Braun, long-time companion of Hitler committed suicide with a cyanide capsule. -Inhibitor of cytochrome c oxidase, part of complex IV of the electron transport chain and inhibits ATP production leading to brain death and heart cessation, hypoxia, and death

Examples of toxicological cases 1988, Saddam Hussein used sarin on Kurds, 1995, Japanese subway sarin attack by terrorist group; 2006 day 5 of “24”—Jack Bauer saves LA from VX attack in TV show; 2013 Assad uses sarin against rebels Sarin and VX are an organophosphorus chemical warfare agents that inhibits acetylcholinesterase, leading to excess acetylcholine and hyperstimulation of neurons, resulting in seizures, tremoring, convulsions, excess salivation, excess tearing, urination, defecation, bronchoconstriction, respiratory failure, death. Sarin

Definitions Toxicology : Is the study of how natural or man-made poisons cause undesirable effects in living organisms. Harmful or adverse effects: Are those that are damaging to either the survival or normal function of the individual. Toxicity : Is the degree to which a substance is poisonous or can cause injury. The toxicity depends on dose, duration and route of exposure ,shape and structure of the chemical itself, and individual human factors.

Definitions Toxic : Toxicant: This term relates to poisonous or deadly effects on the body by inhalation (breathing), ingestion (eating), or absorption, or by direct contact with a chemical. Toxicant: A toxicant is any chemical that can injure or kill humans, animals, or plants, a poison. The term “toxicant” is used when talking about toxic substances that are produced by or are a by-product of human-made activities.

Definitions Toxin : Usually is used when talking about toxic substances produced naturally. A toxin is any poisonous substance of microbial (bacteria or other tiny plants or animals), vegetable, or synthetic chemical origin that reacts with specific cellular components to kill cells, alter growth or development, or kill the organism.

Definitions Selective Toxicity: How Does Toxicity Develop? “Selective toxicity” means that a chemical will produce injury to one kind of living matter without harming another form of life, even though the two may exist close together. How Does Toxicity Develop? Before toxicity can develop, a substance must come into contact with a body surface such as skin, eye or mucosa of the digestive or respiratory tract. How “toxic” an substance can be: The dose of the chemical which comes into contact with .

Sub specialty of toxicology Environmental Toxicology: Is concerned with the study of chemicals that contaminate food, water, soil, or the atmosphere. It also deals with toxic substances that enter bodies of waters such as lakes, streams, rivers, and oceans. This sub-discipline addresses the question of how various plants, animals, and humans are affected by exposure to toxic substances.

Sub specialty of toxicology Occupational (Industrial) Toxicology : Is concerned with health effects from exposure to chemicals in the workplace. This field grew out of a need to protect workers from toxic substances and to make their work environment safe.

Sub specialty of toxicology Food Toxicology: Is involved in delivering a safe and edible supply of food to the consumer. During processing, a number of substances may be added to food to make it look, taste, or smell better. Fats, oils, sugars, starches and other substances may be added to change the texture and taste of food.

Sub specialty of toxicology Clinical Toxicology : Is concerned with diseases and illnesses associated with short term or long term exposure to toxic chemicals. Clinical toxicologists include emergency room physicians who must be familiar with the symptoms associated with exposure to a wide variety of toxic substances in order to administer the appropriate treatment.

Sub specialty of toxicology Forensic Toxicology: Is used to help establish cause and effect relationships between exposure to a drug or chemical and the toxic or lethal effects that result from that exposure.

Classification of Toxic Agents: 1- Heavy Metals Metals differ from other toxic substances in that they are neither created nor destroyed by humans. Their use by humans plays an important role in determining their potential for health effects. Their effect on health could occur through at least two mechanisms: 1-First, by increasing the presence of heavy metals in air, water, soil, and Food. 2-Second, by changing the structure of the chemical. For example, chromium III can be converted to or from chromium VI, the more toxic form of the metal.

Classification of Toxic Agents: 2- Solvents and Vapors: Nearly everyone is exposed to solvents. Occupational exposures can range from the use of “white-out” by administrative personnel, to the use of chemicals by technicians in a nail salon. When a solvent evaporates, the vapors may also pose a threat to the exposed population.

Classification of Toxic Agents: 3-Radiation and Radioactive Materials: Radiation is the release and propagation of energy in space or through a material medium in the form of waves, the transfer of heat or light by waves of energy, or the stream of particles from a nuclear reactor.

Classification of Toxic Agents: 3- Dioxin/Furans: Dioxin, (or TCDD) was originally discovered as a contaminant in the herbicide Agent Orange. Dioxin is also a by-product of chlorine processing in paper producing industries. 4- Pesticides: Any substance or mixture of substances intended to prevent, destroy, repel, or mitigate any pest. Pesticides may also be described as any physical, chemical, or biological agent that will kill an undesirable plant or animal pest.

Classification of Toxic Agents: 5-Plant Toxins : Different portions of a plant may contain different concentrations of chemicals. Some chemicals made by plants can be lethal. For example, taxon, used in chemotherapy to kill cancer cells, is produced by a species of the yew plant. 6-Animal Toxins: These toxins can result from venomous or poisonous animal releases. Venomous animals are usually defined as those that are capable of producing a poison in a highly developed gland or group of cells, and can deliver that toxin through biting or stinging. Poisonous animals are generally regarded as those whose tissues, either in part or in their whole, are toxic.

Subcategories of Toxic Substance Classifications : 1-Effect on target organs (liver, kidney, hematopoietic system). 2- Use (pesticide, solvent, food additive). 3-Source of the agent (animal and plant toxins). 4-Effects (cancer mutation, liver injury). 5-Physical state (gas, dust, liquid). 6-Labeling requirements (explosive, flammable, oxidizer). .(7-Chemistry (aromatic amine, halogenated 8-Poisoning potential (extremely toxic, very toxic, slightly toxic)hydrocarbon).

Factors that affects toxicity -Route of administration. -Duration and frequency of exposure. -Dose or concentration.

Rapidity of response with respect to the route of exposure 1-Intravenous . 2-Inhalation. 3-Intrapertoneally. 4-Subcutanous . 5-Intramuscular . 6-Intradermal . 7-Topical .

Spectrum of toxicity Tolerance : -Allergic reactions. -Chemical allergies. -Idiosyncratic reactions: -immediate vs. delayed toxicity -reversible vs. irreversible toxicity -local vs. systemic toxicity Tolerance : state of decreased responsiveness to a toxic effect of a chemical, resulting from previous exposure dispositional tolerance; a decreased amount of drug reaching the site cellular; reduced responsiveness of a tissue.

Evaluating Dose-Response Relationships ED: Effective dose (therapeutic dose of a drug) TD: Toxic dose (dose at which toxicity occurs) LD: Lethal dose (dose at which death occurs) NOAEL: no observed adverse effect level LOAEL: lowest observed adverse effect level ED50: dose at which 50% of population therapeutically responds. (In this example, ED50=1 mg/kg) TD50: dose at which 50% of population experiences toxicity (TD50=10 mg/kg). LD50: dose at which 50% of population dies (LD50=100 mg/kg).

Comparing Toxicity of Compounds Therapeutic Index (TI) TI = LD50/ED50 or TI = TD50/ED50 TI is the ratio of the doses of the toxic and the desired responses. TI is used as an index of comparative toxicity of two different materials; approximate statement of the relative safety of a drug. The larger the ratio, the greater the relative safety.

References : http://www.atsdr.cdc.gov/training/toxmanual/pdf/module-1.pdf http://toxlearn.nlm.nih.gov/Toxicology/tx010101/tx010101.pdf http://www.toxicology.org/ai/eo/intro_toxslides.asp

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